DOCSLIB.ORG

Regulating Rac in the Nervous System: Molecular Function and Disease Implication of Rac Gefs and Gaps

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Regulating Rac in the Nervous System: Molecular Function and Disease Implication of Rac Gefs and Gaps Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 632450, 17 pages http://dx.doi.org/10.1155/2015/632450 Review Article Regulating Rac in the Nervous System: Molecular Function and Disease Implication of Rac GEFs and GAPs Yanyang Bai, Xiaoliang Xiang, Chunmei Liang, and Lei Shi JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, Jinan University, Guangzhou, Guangdong 510632, China Correspondence should be addressed to Lei Shi; [email protected] Received 23 January 2015; Accepted 6 March 2015 Academic Editor: Akito Tanoue Copyright © 2015 Yanyang Bai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rho family GTPases, including RhoA, Rac1, and Cdc42 as the most studied members, are master regulators of actin cytoskeletal organization. Rho GTPases control various aspects of the nervous system and are associated with a number of neuropsychiatric and neurodegenerative diseases. The activity of Rho GTPases is controlled by two families of regulators, guanine nucleotide exchange factors (GEFs) as the activators and GTPase-activating proteins (GAPs) as the inhibitors. Through coordinated regulation by GEFs and GAPs, Rho GTPases act as converging signaling molecules that convey different upstream signals in the nervous system. So far,morethan70membersofeitherGEFsorGAPsofRhoGTPaseshavebeenidentifiedinmammals,butonlyasmallsubset of them have well-known functions. Thus, characterization of important GEFs and GAPs in the nervous system is crucial for the understanding of spatiotemporal dynamics of Rho GTPase activity in different neuronal functions. In this review, we summarize the current understanding of GEFs and GAPs for Rac1, with emphasis on the molecular function and disease implication of these regulators in the nervous system. 1. Introduction exchange of bound GDP for GTP,enabling them to recognize and activate downstream effectors, and GTPase-activating Rho family GTPases constitute a distinct family of guanine proteins (GAPs), which suppress Rho GTPases by enhancing nucleotide-binding proteins which belongs to the superfam- their intrinsic rate of GTP hydrolysis to GDP. ily of Ras-related GTPases. Rho GTPases are key regulators of Two types of GEFs for Rho GTPases have been identified. the actin cytoskeletal dynamics, play crucial roles in various Dbl-(diffuseB-celllymphoma-)likeGEFs,theclassical aspects of brain development, and are implicated in a number GEFs, are characterized by the presence of a DH (Dbl homol- of neuropsychiatric and neurodegenerative diseases [1–5]. ogy) domain followed by a PH (pleckstrin homology) domain More than 20 mammalian members of Rho family GTPases [8]. The DH domain is known to be responsible for the cata- have been described, including Rho-like (RhoA, RhoB, and lytic exchange activity of Rho GEFs, whereas the PH domain RhoC), Rac-like (Rac1, Rac2, Rac3, and RhoG), Cdc42-like regulates lipid binding and membrane targeting. Another (Cdc42, TC10/RhoQ, TCL/RhoJ, Wrch1/RhoU, and Chp/ type of GEFs is the Dock (dedicator of cytokinesis) family Wrch2/RhoV), Rnd (Rnd1, Rnd2, and Rnd3/RhoE), Rho- atypical GEFs, which contains a Dock homology region BTB (Rho-BTB1 and RhoBTB2), RhoD, Rif/RhoF,and RhoH/ (DHR) 1-DHR2 module instead of the PH-DH module. TTF [6, 7]. Like all GTP-binding proteins, Rho GTPases con- DHR1-DHR2 module plays similar roles as PH-DH module, tain sequence motifs for binding to GDP or GTP, thus acting of which DHR1 is important for the phospholipid-binding as bimolecular switches, cycling between an inactive GDP- and membrane targeting of Docks, and DHR2 is responsible boundstateandanactiveGTP-boundstate.ActivityofRho foritsGEFactivity[9]. On the other hand, Rho GAPs are GTPases is tightly controlled by the coordinated action of two usually large multidomain proteins characterized by the pres- classes of regulatory proteins: guanine nucleotide exchange ence of a conserved Rho GAP domain and various function factors (GEFs), which activate Rho GTPases by catalyzing the domains [10]. A variety of GEFs and GAPs have been 2 BioMed Research International identified to govern the activity of Rho GTPases in neuronal cortical neurons, and both Rac1-regulated leading process development and to be associated with neurological diseases formation and JNK-regulated microtubule organization are [5, 11–13]. implicated in Tiam1-regulated neuronal migration [20]. Rac1 is one of the most well-studied Rho GTPases Moreover, Tiam1 acts as a converging transducer of a whichcontrolsawiderangeofcellulareventsofneuronal number of signals, including neurotrophins (such as nerve morphogenesis and motility [14]. Rac1 is a master protein that growth factor (NGF) and brain-derived neurotrophic factor directs actin polymerization and cytoskeletal changes through (BDNF)), ephrins, and Wnts, to regulate neurite outgrowth activating a series of signaling pathways, thus acting as a and neural differentiation21 [ –24]. Tiam1 is also involved in converging sensor molecule that conveys divergent upstream the development of the myelinating glial cells oligodendro- signals. To understand the spatiotemporally dynamic reg- cytesandSchwanncells,suggestingaroleofTiam1forthe ulation of Rac1 activity in the nervous system, this review myelination of neurons in both central and peripheral ner- summarizes the current findings of more than 30 Rac GEFs vous system [25, 26]. Moreover, the gene expression of Tiam1 (including both the Dbl-like and atypical GEFs) and GAPs isdownregulatedinspecificneuronaltypesinresponseto (Table 1). Both the molecular functions and the disease cocaine and oxygen/glucose deprivation, which is one of relevance of these regulators in the nervous system will be possible molecular changes that cause synaptic structural or discussed. Most of these Rac GEFs or GAPs also act on functional alterations in these pathological conditions [27, other Rho GTPases (such as RhoA or Cdc42) or even other 28]. subfamilies of Ras-related GTPases (such as Ras and Rab). Tiam2, also known as STEF (Sif- and Tiam1-like exchange For these regulators, we will emphasize their actions on Rac factor), is the second member of Tiam protein family. Tiam2 and will try to discuss how their actions on Rac or other is far less studied than Tiam1, and its neuronal function GTPases are differentially regulated. revealed thus far is the regulation of neurite outgrowth [29, 30]. In particular, protein kinase A (PKA) dependent phos- 2. Dbl-Like Rac GEFs phorylation of Tiam2 activates the Rac GEF activity of Tiam2, which is a critical signaling pathway underlying dibutyryl 2.1. Tiam. Tiam1 (T-lymphoma invasion and metastasis 1) is cAMP (dbcAMP) induced neurite extension of neuroblas- one of the most extensively studied Rac GEFs in nervous and toma cells [30]. other systems. Tiam1 is a well-known regulator for synapse formation and plasticity. Tiam1 interacts with both EphB 2.2. Trio and Kalirin. Trio and Kalirin (also known as Duo), receptors and the synaptic neurotransmitter receptors, N- both having several isoforms, are multidomain containing methyl-D-aspartate (NMDA) receptors, at the postsynaptic Rac GEFs that share high sequence homology. Trio is ubiqui- sites [15, 16]. The Rac GEF activity of Tiam1 is upregulated tously expressed and plays critical roles in early development 2+ by CaMKII (Ca /Calmodulin-dependent protein kinase II) of the nervous system, whereas Kalirin is specifically enriched dependent phosphorylation and EphB activation, leading to in brain and elicits essential regulatory effects on synapse elevated Rac1 activity and spine formation [15, 16]. Moreover, morphogenesis and function. Tiam1 forms a complex with Par3 (partitioning defective gene Mice with complete deletion of Trio display embryonic 3), a regulatory protein for cell polarization, and is restricted lethality with malformed myofibers and defective organiza- to the synapse. This regulation is important for the local acti- tions in several brain regions including hippocampus and vation of Rac1 and spine morphogenesis [17]. Interestingly, olfactory bulb [31]. Further characterization of these Trio Tiam1 is also regulated by MAP1B (microtubule-associated knockout mice revealed that Trio transduces signaling from protein1B)andparticipatesinNMDA-inducedlong-term the chemoattractant netrin-1 through binding to the netrin- depression (LTD) through Rac1-dependent endocytosis of 1 receptor DCC (deleted in colorectal cancer), thus guiding AMPA (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic the outgrowth and projection of commissure axons of cortical acid) receptors and spine shrinkage [18]. These seemingly neurons [32]. Trio is tyrosine phosphorylated by Fyn, a mem- contradictory findings of Tiam1 on both spine formation and ber of Src family kinases, in response to netrin-1 stimulation, elimination have been possibly explained by the following which is essential for DCC localization and netrin-induced study. Tiam1 interacts and cooperates with BCR (breakpoint Rac1 activation and axon growth [33]. Moreover, Trio is cluster region), a Rac GAP at the synapse, and the two coun- implicated in NGF-mediated neurite outgrowth via binding teract each other on Rac1 activity and spine morphogenesis to the membrane protein Kidins220/ARMS [34]. Several [19]. This Rac GEF-GAP complex possibly secures a dynamic neuronal isoforms of Trio have been identified
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • The Role of Cdep in the Embryonic Morphogenesis of Drosophila Melanogaster
    The Role of Cdep in the Embryonic Morphogenesis of Drosophila melanogaster Dissertation zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer.nat.) vorgelegt der Fakultät Mathematik und Naturwissenschaften der Technischen Universität Dresden von Anne Morbach Geboren am 05. August 1984 in Nordhausen, Deutschland Eingereicht am 30. Oktober 2015 Die Dissertation wurde in der Zeit von April 2012 bis Oktober 2015 im Max-Planck-Institut für molekulare Zellbiologie und Genetik angefertigt Gutachter: Prof. Dr. Elisabeth Knust Prof. Dr. Christian Dahmann Now, here, you see, it takes all the running you can do, to keep in the same place. Lewis Carroll, Through the Looking-Glass I Contents List of Figures V List of Tables VII Abstract IX List of Abbreviations XI 1 Introduction 1 1.1 Epithelial cell polarity . 1 1.1.1 Cellularization and formation of the primary epithelium . 1 1.1.1.1 Establishment of epithelial polarity and adhesion . 2 1.1.2 The epithelial polarity network . 3 1.1.3 Cell-cell adhesion . 5 1.1.3.1 Adherens junctions . 5 1.1.3.2 Septate junctions . 6 1.2 Epithelial movements in Drosophila embryonic morphogenesis . 6 1.2.1 Epithelial tube formation during Drosophila embryogenesis . 7 1.2.2 Coordinated migration of epithelial sheets during Dros. embryogenesis 7 1.2.2.1 FERM domain proteins in epithelial migration . 9 1.2.2.2 Cdep . 10 1.3 Mutagenesis with the CRISPR/Cas9 system . 12 2 Aim of My PhD Thesis Work 15 3 Preliminary Work 17 4 Results 19 4.1 A screen for novel regulators in Drosophila embryonic morphogenesis .
    [Show full text]
  • Modular and Distinct Plexin-A4/FARP2/Rac1 Signaling Controls Dendrite Morphogenesis
    The Journal of Neuroscience, July 8, 2020 • 40(28):5413–5430 • 5413 Development/Plasticity/Repair Modular and Distinct Plexin-A4/FARP2/Rac1 Signaling Controls Dendrite Morphogenesis Victor Danelon,1* Ron Goldner,2* Edward Martinez,1 Irena Gokhman,2 Kimberly Wang,1 Avraham Yaron,2 and Tracy S. Tran1 1Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, and 2Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel Diverse neuronal populations with distinct cellular morphologies coordinate the complex function of the nervous system. Establishment of distinct neuronal morphologies critically depends on signaling pathways that control axonal and dendritic devel- opment. The Sema3A-Nrp1/PlxnA4 signaling pathway promotes cortical neuron basal dendrite arborization but also repels axons. However, the downstream signaling components underlying these disparate functions of Sema3A signaling are unclear. Using the KRK-AAA novel PlxnA4 knock-in male and female mice, generated by CRISPR/cas9, we show here that the KRK motif in the PlxnA4 cytoplasmic domain is required for Sema3A-mediated cortical neuron dendritic elaboration but is dispensable for inhibitory axon guidance. The RhoGEF FARP2, which binds to the KRK motif, shows identical functional specificity as the KRK motif in the PlxnA4 receptor. We find that Sema3A activates the small GTPase Rac1, and that Rac1 activity is required for dendrite elaboration but not axon growth cone collapse. This work identifies a novel Sema3A-Nrp1/PlxnA4/FARP2/Rac1 signaling pathway that specifi- cally controls dendritic morphogenesis but is dispensable for repulsive guidance events. Overall, our results demonstrate that the divergent signaling output from multifunctional receptor complexes critically depends on distinct signaling motifs, highlighting the modular nature of guidance cue receptors and its potential to regulate diverse cellular responses.
    [Show full text]
  • Supp Table 6.Pdf
    Supplementary Table 6. Processes associated to the 2037 SCL candidate target genes ID Symbol Entrez Gene Name Process NM_178114 AMIGO2 adhesion molecule with Ig-like domain 2 adhesion NM_033474 ARVCF armadillo repeat gene deletes in velocardiofacial syndrome adhesion NM_027060 BTBD9 BTB (POZ) domain containing 9 adhesion NM_001039149 CD226 CD226 molecule adhesion NM_010581 CD47 CD47 molecule adhesion NM_023370 CDH23 cadherin-like 23 adhesion NM_207298 CERCAM cerebral endothelial cell adhesion molecule adhesion NM_021719 CLDN15 claudin 15 adhesion NM_009902 CLDN3 claudin 3 adhesion NM_008779 CNTN3 contactin 3 (plasmacytoma associated) adhesion NM_015734 COL5A1 collagen, type V, alpha 1 adhesion NM_007803 CTTN cortactin adhesion NM_009142 CX3CL1 chemokine (C-X3-C motif) ligand 1 adhesion NM_031174 DSCAM Down syndrome cell adhesion molecule adhesion NM_145158 EMILIN2 elastin microfibril interfacer 2 adhesion NM_001081286 FAT1 FAT tumor suppressor homolog 1 (Drosophila) adhesion NM_001080814 FAT3 FAT tumor suppressor homolog 3 (Drosophila) adhesion NM_153795 FERMT3 fermitin family homolog 3 (Drosophila) adhesion NM_010494 ICAM2 intercellular adhesion molecule 2 adhesion NM_023892 ICAM4 (includes EG:3386) intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)adhesion NM_001001979 MEGF10 multiple EGF-like-domains 10 adhesion NM_172522 MEGF11 multiple EGF-like-domains 11 adhesion NM_010739 MUC13 mucin 13, cell surface associated adhesion NM_013610 NINJ1 ninjurin 1 adhesion NM_016718 NINJ2 ninjurin 2 adhesion NM_172932 NLGN3 neuroligin
    [Show full text]
  • A Draft Map of the Human Proteome
    ARTICLE doi:10.1038/nature13302 A draft map of the human proteome Min-Sik Kim1,2, Sneha M. Pinto3, Derese Getnet1,4, Raja Sekhar Nirujogi3, Srikanth S. Manda3, Raghothama Chaerkady1,2, Anil K. Madugundu3, Dhanashree S. Kelkar3, Ruth Isserlin5, Shobhit Jain5, Joji K. Thomas3, Babylakshmi Muthusamy3, Pamela Leal-Rojas1,6, Praveen Kumar3, Nandini A. Sahasrabuddhe3, Lavanya Balakrishnan3, Jayshree Advani3, Bijesh George3, Santosh Renuse3, Lakshmi Dhevi N. Selvan3, Arun H. Patil3, Vishalakshi Nanjappa3, Aneesha Radhakrishnan3, Samarjeet Prasad1, Tejaswini Subbannayya3, Rajesh Raju3, Manish Kumar3, Sreelakshmi K. Sreenivasamurthy3, Arivusudar Marimuthu3, Gajanan J. Sathe3, Sandip Chavan3, Keshava K. Datta3, Yashwanth Subbannayya3, Apeksha Sahu3, Soujanya D. Yelamanchi3, Savita Jayaram3, Pavithra Rajagopalan3, Jyoti Sharma3, Krishna R. Murthy3, Nazia Syed3, Renu Goel3, Aafaque A. Khan3, Sartaj Ahmad3, Gourav Dey3, Keshav Mudgal7, Aditi Chatterjee3, Tai-Chung Huang1, Jun Zhong1, Xinyan Wu1,2, Patrick G. Shaw1, Donald Freed1, Muhammad S. Zahari2, Kanchan K. Mukherjee8, Subramanian Shankar9, Anita Mahadevan10,11, Henry Lam12, Christopher J. Mitchell1, Susarla Krishna Shankar10,11, Parthasarathy Satishchandra13, John T. Schroeder14, Ravi Sirdeshmukh3, Anirban Maitra15,16, Steven D. Leach1,17, Charles G. Drake16,18, Marc K. Halushka15, T. S. Keshava Prasad3, Ralph H. Hruban15,16, Candace L. Kerr19{, Gary D. Bader5, Christine A. Iacobuzio-Donahue15,16,17, Harsha Gowda3 & Akhilesh Pandey1,2,3,4,15,16,20 The availability of human genome sequence has transformed biomedical research over the past decade. However, an equiv- alent map for the human proteome with direct measurements of proteins and peptides does not exist yet. Here we present a draft map of the human proteome using high-resolution Fourier-transform mass spectrometry.
    [Show full text]
  • Supplementary Table 2
    Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942
    [Show full text]
  • MAP17's Up-Regulation, a Crosspoint in Cancer and Inflammatory
    García-Heredia and Carnero Molecular Cancer (2018) 17:80 https://doi.org/10.1186/s12943-018-0828-7 REVIEW Open Access Dr. Jekyll and Mr. Hyde: MAP17’s up- regulation, a crosspoint in cancer and inflammatory diseases José M. García-Heredia1,2,3 and Amancio Carnero1,3* Abstract Inflammation is a common defensive response that is activated after different harmful stimuli. This chronic, or pathological, inflammation is also one of the causes of neoplastic transformation and cancer development. MAP17 is a small protein localized to membranes with a restricted pattern of expression in adult tissues. However, its expression is common in destabilized cells, as it is overexpressed both in inflammatory diseases and in cancer. MAP17 is overexpressed in most, if not all, carcinomas and in many tumors of mesenchymal origin, and correlates with higher grade and poorly differentiated tumors. This overexpression drives deep changes in cell homeostasis including increased oxidative stress, deregulation of signaling pathways and increased growth rates. Importantly, MAP17 is associated in tumors with inflammatory cells infiltration, not only in cancer but in various inflammatory diseases such as Barret’s esophagus, lupus, Crohn’s, psoriasis and COPD. Furthermore, MAP17 also modifies the expression of genes connected to inflammation, showing a clear induction of the inflammatory profile. Since MAP17 appears highly correlated with the infiltration of inflammatory cells in cancer, is MAP17 overexpression an important cellular event connecting tumorigenesis and inflammation? Keywords: MAP17, Cancer, Inflammatory diseases Background process ends when the activated cells undergo apoptosis in Inflammatory response is a common defensive process acti- a highly regulated process that finishes after pathogens and vated after different harmful stimuli, constituting a highly cell debris have been phagocytized [9].
    [Show full text]
  • Supplementary Table 1
    Supplementary Table 1. 492 genes are unique to 0 h post-heat timepoint. The name, p-value, fold change, location and family of each gene are indicated. Genes were filtered for an absolute value log2 ration 1.5 and a significance value of p ≤ 0.05. Symbol p-value Log Gene Name Location Family Ratio ABCA13 1.87E-02 3.292 ATP-binding cassette, sub-family unknown transporter A (ABC1), member 13 ABCB1 1.93E-02 −1.819 ATP-binding cassette, sub-family Plasma transporter B (MDR/TAP), member 1 Membrane ABCC3 2.83E-02 2.016 ATP-binding cassette, sub-family Plasma transporter C (CFTR/MRP), member 3 Membrane ABHD6 7.79E-03 −2.717 abhydrolase domain containing 6 Cytoplasm enzyme ACAT1 4.10E-02 3.009 acetyl-CoA acetyltransferase 1 Cytoplasm enzyme ACBD4 2.66E-03 1.722 acyl-CoA binding domain unknown other containing 4 ACSL5 1.86E-02 −2.876 acyl-CoA synthetase long-chain Cytoplasm enzyme family member 5 ADAM23 3.33E-02 −3.008 ADAM metallopeptidase domain Plasma peptidase 23 Membrane ADAM29 5.58E-03 3.463 ADAM metallopeptidase domain Plasma peptidase 29 Membrane ADAMTS17 2.67E-04 3.051 ADAM metallopeptidase with Extracellular other thrombospondin type 1 motif, 17 Space ADCYAP1R1 1.20E-02 1.848 adenylate cyclase activating Plasma G-protein polypeptide 1 (pituitary) receptor Membrane coupled type I receptor ADH6 (includes 4.02E-02 −1.845 alcohol dehydrogenase 6 (class Cytoplasm enzyme EG:130) V) AHSA2 1.54E-04 −1.6 AHA1, activator of heat shock unknown other 90kDa protein ATPase homolog 2 (yeast) AK5 3.32E-02 1.658 adenylate kinase 5 Cytoplasm kinase AK7
    [Show full text]
  • Genome-Wide DNA Methylation Dynamics During Epigenetic
    Gómez‑Redondo et al. Clin Epigenet (2021) 13:27 https://doi.org/10.1186/s13148‑021‑01003‑x RESEARCH Open Access Genome‑wide DNA methylation dynamics during epigenetic reprogramming in the porcine germline Isabel Gómez‑Redondo1*† , Benjamín Planells1†, Sebastián Cánovas2,3, Elena Ivanova4, Gavin Kelsey4,5 and Alfonso Gutiérrez‑Adán1 Abstract Background: Prior work in mice has shown that some retrotransposed elements remain substantially methylated during DNA methylation reprogramming of germ cells. In the pig, however, information about this process is scarce. The present study was designed to examine the methylation profles of porcine germ cells during the time course of epigenetic reprogramming. Results: Sows were artifcially inseminated, and their fetuses were collected 28, 32, 36, 39, and 42 days later. At each time point, genital ridges were dissected from the mesonephros and germ cells were isolated through magnetic‑ activated cell sorting using an anti‑SSEA‑1 antibody, and recovered germ cells were subjected to whole‑genome bisulphite sequencing. Methylation levels were quantifed using SeqMonk software by performing an unbiased analysis, and persistently methylated regions (PMRs) in each sex were determined to extract those regions showing 50% or more methylation. Most genomic elements underwent a dramatic loss of methylation from day 28 to day 36, when the lowest levels were shown. By day 42, there was evidence for the initiation of genomic re‑methylation. We identifed a total of 1456 and 1122 PMRs in male and female germ cells, respectively, and large numbers of transpos‑ able elements (SINEs, LINEs, and LTRs) were found to be located within these PMRs. Twenty‑one percent of the introns located in these PMRs were found to be the frst introns of a gene, suggesting their regulatory role in the expression of these genes.
    [Show full text]
  • Genome-Wide Detection of Natural Selection in African Americans Pre- and Post-Admixture
    Downloaded from genome.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Method Genome-wide detection of natural selection in African Americans pre- and post-admixture Wenfei Jin,1 Shuhua Xu,1,6 Haifeng Wang,2 Yongguo Yu,3 Yiping Shen,4,5 Bailin Wu,4,5 and Li Jin1,4,6 1Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences and Max Planck Society (CAS-MPG) Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 2Chinese National Human Genome Center, Shanghai 201203, China; 3Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China; 4Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China; 5Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA It is particularly meaningful to investigate natural selection in African Americans (AfA) due to the high mortality their African ancestry has experienced in history. In this study, we examined 491,526 autosomal single nucleotide poly- morphisms (SNPs) genotyped in 5210 individuals and conducted a genome-wide search for selection signals in 1890 AfA. Several genomic regions showing an excess of African or European ancestry, which were considered the footprints of selection since population admixture, were detected based on a commonly used approach. However, we also developed a new strategy to detect natural selection both pre- and post-admixture by reconstructing an ancestral African population (AAF) from inferred African components of ancestry in AfA and comparing it with indigenous African populations (IAF).
    [Show full text]
  • Egfr Activates a Taz-Driven Oncogenic Program in Glioblastoma
    EGFR ACTIVATES A TAZ-DRIVEN ONCOGENIC PROGRAM IN GLIOBLASTOMA by Minling Gao A thesis submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March 2020 ©2020 Minling Gao All rights reserved Abstract Hyperactivated EGFR signaling is associated with about 45% of Glioblastoma (GBM), the most aggressive and lethal primary brain tumor in humans. However, the oncogenic transcriptional events driven by EGFR are still incompletely understood. We studied the role of the transcription factor TAZ to better understand master transcriptional regulators in mediating the EGFR signaling pathway in GBM. The transcriptional coactivator with PDZ- binding motif (TAZ) and its paralog gene, the Yes-associated protein (YAP) are two transcriptional co-activators that play important roles in multiple cancer types and are regulated in a context-dependent manner by various upstream signaling pathways, e.g. the Hippo, WNT and GPCR signaling. In GBM cells, TAZ functions as an oncogene that drives mesenchymal transition and radioresistance. This thesis intends to broaden our understanding of EGFR signaling and TAZ regulation in GBM. In patient-derived GBM cell models, EGF induced TAZ and its known gene targets through EGFR and downstream tyrosine kinases (ERK1/2 and STAT3). In GBM cells with EGFRvIII, an EGF-independent and constitutively active mutation, TAZ showed EGF- independent hyperactivation when compared to EGFRvIII-negative cells. These results revealed a novel EGFR-TAZ signaling axis in GBM cells. The second contribution of this thesis is that we performed next-generation sequencing to establish the first genome-wide map of EGF-induced TAZ target genes.
    [Show full text]
  • Investigation of Two Early Events in Amyotrophic Lateral Sclerosis
    INVESTIGATION OF TWO EARLY EVENTS IN AMYOTROPHIC LATERAL SCLEROSIS -MRNA OXIDATION AND UP-REGULATION OF A NOVEL PROTECTIVE FACTOR MSUR1 DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Yueming Chang, Bachelor in Medicine *********** The Ohio State University 2007 Dissertation Committee: Approved by Professor Chien-liang Glenn Lin, Advisor Professor Andrej Rotter ------------------------------------------- Professor Arthur H.M. Burghes Advisor Professor John Oberdick The Ohio State Biochemistry Program ABSTRACT Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the spinal cord, motor cortex and brainstem, which typically results in mortality within 2-5 years after the onset of disease. The cause of disease is unknown in the majority of cases, and there is no cure for ALS of the moment. Approximately 5% of ALS cases are familial, and 15-25% of the familial cases are linked to mutation in the gene encoding the antioxidant enzyme Cu 2+ /Zn 2+ superoxide dismutase (SOD1). Overexpression of some of ALS-linked mutant SOD1 proteins in transgenic mice results in the development of a neurological disorder that resembles ALS patients. The transgenic mice expressing mutant SOD1 (G93A) is a commonly used ALS animal model. This dissertation demonstrates two early events occurred in the pre-symptomatic stage of SOD1 (G93A) mice, including RNA oxidation and up-regulation of a novel protective factor MSUR1 (mutant SOD1-upregulated RNA 1). Accumulating evidence indicates that messenger RNA (mRNA) oxidation may be associated with neuronal deterioration during the process of neurodegeneration.
    [Show full text]